The currently available clinical antidepressants can be classified into 13 different classes based on their mechanisms of action. These basic pharmacological concepts thoroughly elucidate and unravel the therapeutic actions and side effects of the wide range of antidepressants currently available. The two classical mechanisms are exhibited by tricyclic antidepressants (TCAs) and by monoamine oxidase inhibitors (MAOIs). Regarding the 11 relatively nonclassical antidepressants, the most widely prescribed agents are the selective serotonin reuptake inhibitors (SSRIs). The mechanisms of action for the other classes of antidepressants that exhibit additional actions on serotonergic neurotransmission are dual serotonin-norepinephrine reuptake inhibition (SNRI), serotonin receptors antagonism with serotonin reuptake inhibition (SARI), serotonin 5-HT1Aautoreceptor partial agonism with serotonin reuptake inhibition (SPARI), serotonin-norepinephrine reuptake inhibition and serotonin receptors antagonism antidepressant with potent antipsychotic D2 receptor blockade/antagonism (SNRISA with potent antipsychotic D2 receptor blockade/antagonism), norepinephrine reuptake inhibition with serotonin receptors antagonism (NRISA), noradrenergic α2-receptor antagonism with specific serotonergic receptors-2 and-3 antagonism (NASSA), and atypical antipsychotics that exhibit weak D2receptor antagonism with potently strong 5-HT2Areceptor blockade. Furthermore, the two classes that exhibit selective norepinephrine reuptake inhibition (NRI) and dual norepinephrine-dopamine reuptake inhibition (NDRI) define separate novel classes of antidepressants that have a direct action on the noradrenergic neurotransmission system but have no direct action on the serotonergic neurotransmission system, while the last remaining one class of N-methyl-D-aspartate-glutamatergic ionoceptor antagonist/inverse agonist/partial agonist also represents a separate novel class of antidepressants with a direct action on the excitatory glutamatergic neurotransmission system but no direct action on the serotonergic, noradrenergic, or dopaminergic neurotransmission systems. Lastly, this review remarkably advocates for the incorporation of the atypical antipsychotics and NMDA-glutamatergic ionoceptor antagonist/inverse agonist/partial agonist as new member classes of the antidepressant agents because of their clinically significant roles in the management of depression disorders.